Therapeutic prime/pull vaccination of HSV-2-infected guinea pigs with the ribonucleotide reductase 2 (RR2) protein and CXCL11 chemokine boosts antiviral local tissue-resident and effector memory CD4+ and CD8+ T cells and protects against recurrent genital herpes.

Following acute herpes simplex virus type 2 (HSV-2) infection, the virus undergoes an asymptomatic latent infection of sensory neurons of dorsal root ganglia (DRG). Chemical and physical stress cause intermittent virus reactivation from latently infected DRG and recurrent virus shedding in the genital mucosal epithelium causing genital herpes in symptomatic patients. While T cells appear to play a role in controlling virus reactivation from DRG and reducing the severity of recurrent genital herpes, the mechanisms for recruiting these T cells into DRG and the vaginal mucosa (VM) remain to be fully elucidated. The present study investigates the effect of CXCL9, CXCL10, and CXCL11 T-cell-attracting chemokines on the frequency and function of DRG- and VM-resident CD4+ and CD8+ T cells and its effect on the frequency and severity of recurrent genital herpes in the recurrent herpes guinea pig model. HSV-2 latent-infected guinea pigs were immunized intramuscularly with the HSV-2 ribonucleotide reductase 2 (RR2) protein (Prime) and subsequently treated intravaginally with the neurotropic adeno-associated virus type 8 expressing CXCL9, CXCL10, or CXCL11 chemokines to recruit CD4+ and CD8+ T cells into the infected DRG and VM (Pull). Compared to the RR2 therapeutic vaccine alone, the RR2/CXCL11 prime/pull therapeutic vaccine significantly increased the frequencies of functional tissue-resident and effector memory CD4+ and CD8+ T cells in both DRG and VM tissues. This was associated with less virus in the healed genital mucosal epithelium and reduced frequency and severity of recurrent genital herpes. These findings confirm the role of local DRG- and VM-resident CD4+ and CD8+ T cells in reducing virus shedding at the vaginal site of infection and the severity of recurrent genital herpes and propose the novel prime-pull vaccine strategy to protect against recurrent genital herpes.IMPORTANCEThe present study investigates the novel prime/pull therapeutic vaccine strategy to protect against recurrent genital herpes using the latently infected guinea pig model. In this study, we used the strategy that involves immunization of herpes simplex virus type 2-infected guinea pigs using a recombinantly expressed herpes tegument protein-ribonucleotide reductase 2 (RR2; prime), followed by intravaginal treatment with the neurotropic adeno-associated virus type 8 expressing CXCL9, CXCL10, or CXCL11 T-cell-attracting chemokines to recruit T cells into the infected dorsal root ganglia (DRG) and vaginal mucosa (VM) (pull). We show that the RR2/CXCL11 prime-pull therapeutic vaccine strategy elicited a significant reduction in virus shedding in the vaginal mucosa and decreased the severity and frequency of recurrent genital herpes. This protection was associated with increased frequencies of functional tissue-resident (TRM cells) and effector (TEM cells) memory CD4+ and CD8+ T cells infiltrating latently infected DRG tissues and the healed regions of the vaginal mucosa. These findings shed light on the role of tissue-resident and effector memory CD4+ and CD8+ T cells in DRG tissues and the VM in protection against recurrent genital herpes and propose the prime-pull therapeutic vaccine strategy in combating genital herpes.

Development of recombinant rotavirus carrying herpes simplex virus 2 glycoprotein D gene based on reverse genetics technology.

Vaccine development for herpes simplex virus 2 (HSV-2) has been attempted, but no vaccines are yet available. A plasmid-based reverse genetics system for Rotavirus (RV), which can cause gastroenteritis, allows the generation of recombinant RV containing foreign genes. In this study, we sought to develop simian RV (SA11) as a vector to express HSV-2 glycoprotein D (gD2) and evaluated its immunogenicity in mice. We generated the recombinant SA11-gD2 virus (rSA11-gD2) and confirmed its ability to express gD2 in vitro. The virus was orally inoculated into suckling BALB/c mice and into 8-week-old mice. Serum IgG and IgA titers against RV and gD2 were measured by ELISA. In the 8-week-old mice inoculated with rSA11-gD2, significant increases in not only antibodies against RV but also IgG against gD2 were demonstrated. In the suckling mice, antibodies against RV were induced, but gD2 antibody was not detected. Diarrhea observed after the first inoculation of rSA11-gD2 in suckling mice was similar to that induced by the parent virus. A gD2 expressing simian RV recombinant, which was orally inoculated, induced IgG against gD2. This strategy holds possibility for genital herpes vaccine development.

Building gender-specific sexually transmitted infection risk prediction models using CatBoost algorithm and NHANES data.

BACKGROUND AND AIMS: Sexually transmitted infections (STIs) are a significant global public health challenge due to their high incidence rate and potential for severe consequences when early intervention is neglected. Research shows an upward trend in absolute cases and DALY numbers of STIs, with syphilis, chlamydia, trichomoniasis, and genital herpes exhibiting an increasing trend in age-standardized rate (ASR) from 2010 to 2019. Machine learning (ML) presents significant advantages in disease prediction, with several studies exploring its potential for STI prediction. The objective of this study is to build males-based and females-based STI risk prediction models based on the CatBoost algorithm using data from the National Health and Nutrition Examination Survey (NHANES) for training and validation, with sub-group analysis performed on each STI. The female sub-group also includes human papilloma virus (HPV) infection. METHODS: The study utilized data from the National Health and Nutrition Examination Survey (NHANES) program to build males-based and females-based STI risk prediction models using the CatBoost algorithm. Data was collected from 12,053 participants aged 18 to 59 years old, with general demographic characteristics and sexual behavior questionnaire responses included as features. The Adaptive Synthetic Sampling Approach (ADASYN) algorithm was used to address data imbalance, and 15 machine learning algorithms were evaluated before ultimately selecting the CatBoost algorithm. The SHAP method was employed to enhance interpretability by identifying feature importance in the model's STIs risk prediction. RESULTS: The CatBoost classifier achieved AUC values of 0.9995, 0.9948, 0.9923, and 0.9996 and 0.9769 for predicting chlamydia, genital herpes, genital warts, gonorrhea, and overall STIs infections among males. The CatBoost classifier achieved AUC values of 0.9971, 0.972, 0.9765, 1, 0.9485 and 0.8819 for predicting chlamydia, genital herpes, genital warts, gonorrhea, HPV and overall STIs infections among females. The characteristics of having sex with new partner/year, times having sex without condom/year, and the number of female vaginal sex partners/lifetime have been identified as the top three significant predictors for the overall risk of male STIs. Similarly, ever having anal sex with a man, age and the number of male vaginal sex partners/lifetime have been identified as the top three significant predictors for the overall risk of female STIs. CONCLUSIONS: This study demonstrated the effectiveness of the CatBoost classifier in predicting STI risks among both male and female populations. The SHAP algorithm revealed key predictors for each infection, highlighting consistent demographic characteristics and sexual behaviors across different STIs. These insights can guide targeted prevention strategies and interventions to alleviate the impact of STIs on public health.

Herpes Simplex Virus: A Practical Guide to Diagnosis, Management, and Patient Counseling for the Primary Care Clinician.

Genital herpes is a chronic, lifelong sexually transmitted viral infection, which can cause recurrent, self-limited genital ulcers. It is caused by herpes simplex virus (HSV) type 1 and type 2 viruses. Genital HSV infection is a very prevalent STI, which causes self-limited, recurrent genital ulcers. Treatment decreases duration of symptoms and signs and can be provided as episodic or suppressive therapy. Genital herpes can have a substantial impact during pregnancy and on sexual health in general. Counseling on natural history, transmission, treatment, and management of sexual partners is an integral part of management of genital herpes.

Sepsis and multi-organ failure due to genital herpes in a healthy person.

Herpes simplex virus type 2 (HSV-2) is highly prevalent in several regions of the world and is the main pathogen causing genital herpes, which is transmitted almost exclusively through sexual contact. Systemically disseminated infections caused by HSV-2 are rare and most often seen in newborns, pregnant women, or immunocompromised populations. The virus can invade multiple organs and cause damage. In this paper, we present an extremely rare case of an immunocompetent 36-year-old male who came to our hospital with a high fever with abdominal pain and died of sepsis and multiple organ dysfunction syndrome within a short period. After the exclusion of common pathogens such as bacterial and fungal infections during hospitalization, metagenomic next generation sequencing of the patient's peripheral blood and ascites gave us the answer, and very high nucleic acid sequence counts of HSV-2 were detected in both his peripheral blood and ascites, confirming HSV-2 as the causative virus. In addition, this paper provides a brief review of the relevant literature.

Expansion of the HSV-2-specific T cell repertoire in skin after immunotherapeutic HSV-2 vaccine.

The skin at the site of HSV-2 reactivation is enriched for HSV-2-specific T cells. To evaluate whether an immunotherapeutic vaccine could elicit skin-based memory T cells, we studied skin biopsies and HSV-2-reactive CD4+ T cells from PBMCs by T cell receptor (TCR) ß chain (TRB) sequencing before and after vaccination with a replication-incompetent whole-virus HSV-2 vaccine candidate (HSV529). The representation of HSV-2-reactive CD4+ TRB sequences from PBMCs in the skin TRB repertoire increased after the first vaccine dose. We found sustained expansion after vaccination of unique, skin-based T cell clonotypes that were not detected in HSV-2-reactive CD4+ T cells isolated from PBMCs. In one participant, a switch in immunodominance occurred with the emergence of a TCR αß pair after vaccination that was not detected in blood. This TCRαß was shown to be HSV-2 reactive by expression of a synthetic TCR in a Jurkat-based NR4A1 reporter system. The skin in areas of HSV-2 reactivation possessed an oligoclonal TRB repertoire that was distinct from the circulation. Defining the influence of therapeutic vaccination on the HSV-2-specific TRB repertoire requires tissue-based evaluation.

Twenty years of herpes simplex virus type 2 (HSV-2) research in low-income and middle-income countries: systematic evaluation of progress made in addressing WHO prioritiesfor research in HSV-2 epidemiology and diagnostics.

INTRODUCTION: Low-income and middle-income countries (LMICs) have a high burden of herpes simplex virus type 2 (HSV-2) infection, which has been strongly associated with HIV. In 2001, the WHO hosted a workshop to set research priorities for HSV-2 in LMICs. Periodic re-evaluation of research priorities is essential to ensure effective allocation of resources. This study describes the progress made between 2000 and 2020 in addressing the priorities identified in two of the five thematic areas that were the workshop's focus: HSV-2 epidemiology and diagnostics. The remaining areas are addressed in a companion paper. METHODS: A systematic search of MEDLINE, CINAHL, Global Health and Cochrane databases was carried out. Relevant primary and secondary research studies conducted in LMICs, written in English and published from 2000-2020 were included. Two independent researchers screened, identified papers and extracted preidentified variables from study texts. Data were organised into an Excel spreadsheet and analysed using IBM SPSS V.26. RESULTS: Overall, 4445 discrete papers were identified, of which 165 publications were eligible for inclusion. The highest general population HSV-2 prevalence was reported in South and West Africa. Prevalence was higher among women than men and increased with age. HSV-2 prevalence studies among key populations were few, and the majority were in East and South Asia. Cohort studies of HSV-2 incidence among younger populations (mean age=25 years) and HSV-2 infection prevalence in North Africa and the Middle East were few. The most researched topic in HSV-2 diagnostics addressed serological techniques and direct molecular biology. Studies of point-of-care testing were also few. CONCLUSION: HSV-2 research identified in LMICs has mainly addressed the epidemiology and diagnostics priorities identified by the 2001 WHO workshop. Unaddressed priorities include point-of-care testing, antiviral resistance and exploration of HSV-2 epidemiology in neglected geographical settings and population subgroups.

Vaccine value profile for herpes simplex virus.

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are chronic, highly prevalent viral infections that cause significant morbidity around the world. HSV-2 is sexually transmitted and is the leading cause of genital ulcer disease (GUD). It also increases the risk of HIV acquisition, fueling the HIV epidemic. HSV-1 is typically acquired in childhood through nonsexual contact and contributes to oral and ocular disease, but it can also be sexually transmitted to cause GUD. Both HSV-1 and HSV-2 cause neonatal herpes and neurologic disease. Given the ubiquitous nature of HSV-1 and HSV-2 infections and the limited existing prevention and control measures, vaccination would be the most efficient strategy to reduce the global burden of morbidity related to HSV infection. Vaccine strategies include prophylactic vaccination, which would prevent infection among susceptible persons and would likely be given to adolescents, and therapeutic vaccinations, which would be given to people with symptomatic genital HSV-2 infection. This document discusses the vaccine value profile of both types of vaccines. This 'Vaccine Value Profile' (VVP) for HSV is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by subject matter experts from academia, non-profit organizations, government agencies and multi-lateral organizations. All contributors have extensive expertise on various elements of the HSV VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

20 years of herpes simplex virus type 2 (HSV-2) research in low-income and middle-income countries: systematic evaluation of progress made in addressing WHO priorities for research in HSV-2/HIV interactions, HSV-2 control and mathematical modelling.

INTRODUCTION: Reviewing and updating research priorities is essential to assess progress and to ensure optimal allocation of financial and human resources in research. In 2001, WHO held a research priority setting workshop for herpes simplex virus type 2 (HSV-2) research in low-income and middle-income countries (LMICs). This study aimed to describe progress between 2000 and 2020 in three of the five key research priority areas outlined in the workshop: HSV-2/HIV interactions, HSV-2 control measures and HSV-2 mathematical modelling. The remaining priorities are addressed in a companion paper. METHOD: A systematic literature search of MEDLINE, CINAHL, Global Health and Cochrane databases was carried out. Relevant primary research studies based in LMICs, written in English and published on 2000-2020 were included. Papers were screened by two independent reviewers, and suitable variables were selected for manual extraction from study texts. Data were organised into an Excel spreadsheet and analysed using IBM SPSS. RESULTS: In total, 3214 discrete papers were identified, of which 180 were eligible for inclusion (HSV-2/HIV interactions, 98; control measures, 58; mathematical modelling, 24). Most studies were conducted in East Africa. The majority of the 2001 WHO HSV-2 research priorities were addressed at least in part. Overall, despite several studies describing a strong relationship between HSV-2 and the acquisition and transmission of HIV, HSV-2 control repeatedly demonstrated little effect on HIV shedding or transmission. Further, although mathematical modelling predicted that vaccines could significantly impact HSV-2 indicators, HSV-2 vaccine studies were few. Studies of antiviral resistance were also few. CONCLUSION: Since 2000, LMIC HSV-2 research addressing its control, HIV interactions and mathematical modelling has largely addressed the priorities set in the 2001 WHO HSV-2 workshop. However, key knowledge gaps remain in vaccine research, antiviral cost-effectiveness, antiviral resistance and specific geographical areas.

Disparities in burden of herpes simplex virus type 2 in China: systematic review, meta-analyses, and meta-regressions.

Background: The rising prevalence of herpes simplex type 2 (HSV-2) infection poses a growing global public health challenge. A comprehensive understanding of its epidemiology and burden disparities in China is crucial for informing targeted and effective intervention strategies in the future. Methods: We followed Cochrane and PRISMA guidelines for a systematic review and included publications published in Chinese and English bibliographic systems until March 31st, 2024. We synthesized HSV-2 seroprevalence data across different population types. We used random-effects models for meta-analyses and conducted meta-regression to assess the association between population characteristics and seroprevalence. Results: Overall, 23,999 articles were identified, and 402 publications (1,203,362 participants) that reported the overall seroprevalence rates (858 stratified measures) were included. Pooled HSV-2 seroprevalence among the general population (lower risk) was 7.7% (95% CI: 6.8-8.7%). Compared to the general population, there is a higher risk of HSV-2 prevalence among intermediate-risk populations (14.8%, 95% CI: 11.0-19.1%), and key populations (31.7%, 95% CI: 27.4-36.1%). Female sexual workers (FSWs) have the highest HSV-2 risk (ARR:1.69, 95% CI: 1.61-1.78). We found northeastern regions had a higher HSV-2 seroprevalence than other regions (17.0%, 95% CI: 4.3-35.6%, ARR: 1.38, 95% CI: 1.26-1.50, Northern China as the reference group). This highlighted the disparity by population risk levels and regions. We also found lower HSV-2 prevalence estimates in publications in Chinese bibliographic databases than those in English databases among key populations (such as MSM and HIV-discordant populations). Conclusion: There is a gradient increase in HSV-2 prevalence risk stratification. We also identified region, population, and age disparities and heterogeneities by publication language in the HSV-2 burden. This study provides guidance for future HSV-2 prevention to eliminate disparities of HSV-2 infection and reduce overall HSV-2 burden. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=408108, identifier CRD42023408108.

An unusual co-reactivation of herpes genitalis and shingles in a young male with primary genital herpes in partner.

BACKGROUND: Herpes simplex virus type 2 (HSV-2) is the most common cause of genital ulcers in industrialized countries. Herpes zoster (HZ) is an acute, cutaneous viral infection caused by the reactivation of the varicella-zoster virus (VZV). CASE SUMMARY: A 27-year-old male presented with painful vesicles over the trunk for the last 5 days with painful genital erosions for the last 2 days. His spouse also developed painful genital erosions with systemic complaints for the last 2 days. VZV Polymerase Chain reaction (PCR) from trunk vesicles and type-specific anti-HSV antibody from serum were positive from the index case. DISCUSSION: Here, we report an unusual case of co-reactivation of herpes zoster and genitalis in an immunocompetent male. We recommend the use of molecular testing to confirm the diagnosis of VZV or HSV infection in all cases of genital herpes-like lesions to exclude multi-segmental herpes zoster.

Local Power: The Role of Tissue-Resident Immunity in Human Genital Herpes Simplex Virus Reactivation.

From established latency, human herpes virus type 2 (HSV-2) frequently reactivates into the genital tract, resulting in symptomatic ulcers or subclinical shedding. Tissue-resident memory (TRM) CD8+ T cells that accumulate and persist in the genital skin at the local site of recrudescence are the "first responders" to viral reactivation, performing immunosurveillance and containment and aborting the ability of the virus to induce clinical lesions. This review describes the unique spatiotemporal characteristics, transcriptional signatures, and noncatalytic effector functions of TRM CD8+ T cells in the tissue context of human HSV-2 infection. We highlight recent insights into the intricate overlaps between intrinsic resistance, innate defense, and adaptive immunity in the tissue microenvironment and discuss how rapid virus-host dynamics at the skin and mucosal level influence clinical outcomes of genital herpes diseases.

Korean sexually transmitted infection guidelines 2023 revision, guideline update of viral infections: Genital herpes and anogenital warts.

The Korean Association of Urogenital Tract Infection and Inflammation and the Korea Disease Control and Prevention Agency regularly update, revise, and develop new content for the Korean sexually transmitted infection (STI) guidelines. These professional bodies respond to changing epidemiological trends and evolving scientific evidence, and consider advances in laboratory diagnostics and research. The principal recommendations of the 2023 Korean STI guidelines in terms of viral infection follow: 1) If genital herpes recurs more than 4-6 times annually, suppressive therapy with acyclovir 400 mg orally 2 times/day or famciclovir 250 mg orally 2 times/day or valacyclovir 500 mg orally once a day (for patients with <10 episodes/year) or valacyclovir 1 g orally once daily (for patients with ≥10 episodes/year) is recommended to prevent recurrence; 2) molecular human papillomavirus (HPV) testing is not recommended as a routine test for STI status, nor for determination of HPV vaccination status; and 3) patients should inform their current sexual partners about anogenital warts because the types of HPV that cause such warts can be passed to partners. These guidelines will be updated every 5 years and will be revised when new knowledge on STIs becomes available and there is a reasonable need to improve the guidelines. Physicians and other healthcare providers can use the guidelines to assist in the prevention and treatment of STIs.

Gene editing for latent herpes simplex virus infection reduces viral load and shedding in vivo.

Anti-HSV therapies are only suppressive because they do not eliminate latent HSV present in ganglionic neurons, the source of recurrent disease. We have developed a potentially curative approach against HSV infection, based on gene editing using HSV-specific meganucleases delivered by adeno-associated virus (AAV) vectors. Gene editing performed with two anti-HSV-1 meganucleases delivered by a combination of AAV9, AAV-Dj/8, and AAV-Rh10 can eliminate 90% or more of latent HSV DNA in mouse models of orofacial infection, and up to 97% of latent HSV DNA in mouse models of genital infection. Using a pharmacological approach to reactivate latent HSV-1, we demonstrate that ganglionic viral load reduction leads to a significant decrease of viral shedding in treated female mice. While therapy is well tolerated, in some instances, we observe hepatotoxicity at high doses and subtle histological evidence of neuronal injury without observable neurological signs or deficits. Simplification of the regimen through use of a single serotype (AAV9) delivering single meganuclease targeting a duplicated region of the HSV genome, dose reduction, and use of a neuron-specific promoter each results in improved tolerability while retaining efficacy. These results reinforce the curative potential of gene editing for HSV disease.

The association between alcohol consumption and herpes simplex virus type 2: A cross-sectional study from national health and nutrition examination survey 2009-2016.

BACKGROUND: The current prevalence of Herpes simplex virus type 2 (HSV-2) infection is notably high, with individuals afflicted by HSV-2 facing recurrent outbreaks, challenges in achieving remission, and an elevated risk of HIV infection. This study aims to investigate the relationship between alcohol consumption and HSV-2 infection. METHODS: The data for this study were sourced from 7257 participants who took part in the National Health and Nutrition Examination Survey (NHANES) from 2009 to 2016. The target population consisted of adults with reliable HSV-2 plasma results, and alcohol consumption was assessed using self-report methods. We evaluated the odds ratio (OR) and 95% confidence interval (CI) for the association between alcohol consumption and HSV-2 infection. These estimations were derived from a logistic regression model that was adjusted for key confounding factors. Subgroup analysis specifically focused on alcohol consumption, and the interaction between HSV-2 infection, alcohol consumption, and other variables was assessed through stratified analysis. RESULTS: Among the 7,257 participants included, 89.8% (6,518/7,257) reported varying levels of alcohol consumption history. Compared to individuals who never drinkers, the adjusted odds ratios (ORs) for former drinkers, light drinkers, moderate drinkers, and heavy drinkers were 1.79 (95% CI: 1.34-2.4, p < 0.001), 1.38 (95% CI: 1.07-1.77, p = 0.012), 1.49 (95% CI: 1.15-1.94, p = 0.003), and 1.47 (95% CI: 1.14-1.9, p = 0.003), respectively. The results remained stable in subgroup analyses and sensitivity analyses. CONCLUSION: Current research indicates that individuals with a history of alcohol consumption exhibit a higher risk of HSV-2 infection compared to those who have never drinkers.